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Duan et al BMC Cancer (2022) 22 271 https //doi org/10 1186/s12885 022 09399 2 RESEARCH The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients w[.]
(2022) 22:271 Duan et al BMC Cancer https://doi.org/10.1186/s12885-022-09399-2 Open Access RESEARCH The efficacy of human epidermal growth factor receptor (HER2) blockade switching mode in refractory patients with HER2‑positive metastatic breast cancer: a phase II, multicenter, single‑arm study (SYSUCC‑005) Fangfang Duan1†, Muyi Zhong2†, Yuyu Ma1†, Chenge Song1†, Lehong Zhang3, Ying Lin4, Zhiyong Wu5, Yuanqi Zhang6, Jiajia Huang1, Fei Xu1, Yanxia Shi1, Shusen Wang1, Zhongyu Yuan1, Wen Xia1* and Xiwen Bi1* Abstract Background: Despite significant survival improvement in human epidermal growth factor receptor (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer Methods: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1–14) or vinorelbine (25 mg/m2 intravenously once per day on days and 8) of each 21-day cycle The primary endpoint was progression-free survival (PFS) Results: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151–2.450, P = 0.007) were independent prognostic factors for PFS The most common grade ≥ 3 adverse events were diarrhea (3.8%) and handfoot syndrome (9.4%) Conclusion: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer Trial registration: This trial was registered on ClinicalTrials.gov (NCT02362958) on 13/02/2015 *Correspondence: xiawen@sysucc.org.cn; bixw@sysucc.org.cn † Fangfang Duan, Muyi Zhong, Yuyu Ma and Chenge Song contributed equally as co-first authors Department of Medical Oncology, Sun Yat‑Sen University Cancer Center, The State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangdong 510060 Guangzhou, China Full list of author information is available at the end of the article © The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data Duan et al BMC Cancer (2022) 22:271 Page of Keywords: HER2-positive breast cancer, Trastuzumab refractory, Lapatinib, HER2 blockade therapy Introduction Amplification of human epidermal growth factor receptor (HER2) occurs in nearly 25% of all breast cancer types and enhances its aggressiveness [1, 2] Trastuzumab, a humanized murine IgG monoclonal HER2 antibody, has significantly improved the survival of patients with HER2-positive metastatic breast cancer [3, 4] In the first- line setting, trastuzumab and pertuzumab plus taxane is recommended as the standard care for HER2-positive metastatic breast cancer [5, 6] However, de novo or acquired resistance to anti-HER2 in inevitable, although subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable when other anti-HER2 treatment unavailable, its survival efficacy is limited [7] Trastuzumab emtansine (TDM1) is generally recommended as the standard secondline care by National Comprehensive Clinical Network (NCCN) guidelines for patients rapidly progressing during previous trastuzumab-based treatment [8, 9] But in developing area including China, TDM1 in second-line metastatic setting is difficult to afford due to limited medical insurance, continuing trastuzumab plus chemotherapy remains to be recommend as an appropriate intervention Lapatinib (Tykerb), an orally active, small molecule, reversible tyrosine kinase inhibitor targeting HER2, has been proven to not have cross-resistance with trastuzumab [10, 11] For patients rapidly developing progression during previous trastuzumab-based regimens, continuing anti-HER2 with trastuzumab or switching to lapatinib plus chemotherapeutic drugs was proven effective and recommended as available interventions in second-line setting instead of TDM1 [12–15] However, no compelling and sufficient evidence indicates which one is more effective Given these findings, we conducted this study (SYSUCC-005) to explore the efficacy and safety of switching treatment mode in patients with HER2-positive refractory metastatic breast cancer Methods Study design The SYSUCC-005 trial (NCT02362958) is an open-label, multicenter, phase II, single-arm study for evaluating the efficacy and safety of switching anti-HER2 therapy mode in women with HER2-positive refractory metastatic breast cancer who rapidly progressed during prior adjuvant/first-line trastuzumab, which was conducted in accordance with the Declaration of Helsinki and good clinical practice (GCP) guidelines The ethics committee of Sun Yat-sen University Cancer Center (SYSUCC) reviewed and approved this study protocol before implementation, and every patient provided written informed consent prior to enrollment Patient eligibility Eligible patients were females aged 18 to 75 years with pathologically confirmed metastatic breast cancer HER2 positivity refers to a score of 3 + or 2 + by immunohistochemistry (IHC) with ERBB2 gene amplification on fluorescence in situ hybridization (FISH) Patients were required to have or Eastern Cooperative Oncology Group (ECOG) performance status, and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [16] Patients were considered refractory to trastuzumab if they recurred during or within 12 months after completing adjuvant trastuzumab or rapidly progressed in the first radiological evaluation during first-line trastuzumab for metastatic disease [17] A life expectancy of at least 12 weeks, adequate hematologic, hepatic, renal, and cardiac function, and prior chemotherapy with anthracycline and/or taxane were required Key exclusion criteria included left ventricular ejection fraction (LVEF)